VOLUME: 10 - ISSUE: JAN 2015 |

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Inside this issue

3 News Uptoday 24 New Guidance 34 Audit Findings 483 Observations

- Teva Parenteral Medicines Inc (Jul-2009) - Hovione API facility in Portugal - Impax Hit With Another FDA 483

38 Warning Letters

- Novacyl Wuxi Pharmaceutical Co., Ltd.

40 EMA Non-Compliance Reports

- Medreich Limited – Unit V - Sri Krishna Pharmaceuticals Ltd., Hyderabad, India

43 Regulations of the Month § 211.188 Batch production and control records

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News Uptoday

MHRA says it will review plans for new UK pharma plants free of charge

Expert advice was key to pursuading AstraZeneca to build a £120m ($188m)

manufacturing plant in the UK according to the MHRA, which says the same help is

available to all drugmakers free of charge.

When AstraZeneca choose a Macclesfield site for its Zoladex delivery device manufacturing

plant last November, the news was greeted as an indication the drugmaker intended to keep a

presence in the UK despite previous cutbacks at sites in Alderly Parkand Brixham.

UK chancellor George Osborne called the investment ―great news for the community‖

describing it as something he and Macclesfield MP David Rutley had ―fought really hard along

with the local council and local people to achieve.‖

Another factor that prompted AstraZeneca to build in the UK was advice provided by the MHRA

according to Gerald Heddell, director of inspection, enforcement and standards, who told in-

Pharmatechnologist.com the decision to seek regulatory help early, speeded up the planning

process.

―Both plants constructed with less MHRA collaboration and those with full involvement, must

ultimately meet the necessary standards but in the case of AstraZeneca the early intervention

allowed them to meet their targets more quickly.‖

Heddell explained that AstraZeneca approached the MHRA for a review of the construction plan

that involved site visits, manufacturing technology assessments and detailed analysis of its

validation strategy.

He also said that: ―The Government encourages us as a general rule to support innovation in

medicine. However AstraZeneca came to us independently of any government advice.‖

The approach differs from when fellow UK Big Pharma firm GSK decided to invest £370m in a

manufacturing plant in Ulverston, Cumbria. The UK firm only confirmed the investment after the

Government introduced tax cuts the firm had lobbied for for several years.

GSK's investment decision also followed CEO Andrew Witty‘s receipt of a Knighthood in the

2012 honours list.

MHRA says quality system deficiencies are most common issue from inspections

Deficiencies related to manufacturers’ quality systems are by far the most prevalent

issue cited from inspections by the UK’s MHRA (Medicines and Healthcare Products

Regulatory Agency), the agency said in a report on 2013 inspections

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The agency broke down its inspection work over the last five years and found that the ratio of

major deficiencies raised per inspection has remained relatively constant, and even decreased

since 2009. But the ratio of critical deficiencies remained constant until 2013, when the agency

reported ―a cluster of data integrity issues with potential impact to public health.‖

Data integrity issues -- both as a result of bad practice and to ―a significantly lesser extent

intentional fraud‖ -- have been observed by the agency across all locations and sectors of the

industry. ―There will therefore be a focus on this area during inspections in the near future,‖ the

agency says.

The MHRA also observed that the relative number of critical deficiencies raised per inspection

in a given continent is higher in Asia than the other continents.

In addition, the most frequently encountered defect categories raised over the previous five

years have remained relatively consistent, though there has been a significant increase in

physical or chemical contaminations.

―There has been a general trend towards higher potency active substances, therefore

increasing the potential for a contamination event to have a greater impact,‖ the MHRA says.

The analysis observed 630 GMP inspections in 2013, 216 of which resulted in major or critical

deficiencies and 174 of those were in the UK while 42 were overseas.

Quality Systems

In offering examples of quality system deficiencies, the MHRA cited the following:

No self-inspections carried out in the previous year, nor was there a programme

established for the current year;

Quality system was not being maintained in that Product Quality Reviews had not been

completed during the required period and a significant number of SOPs were past their

review date, among other things; and

The laboratory pharmaceutical quality system was silent with respect to stability sample

management.

Dr Reddy's API plant receives USFDA 483 with nine observations

Dr Reddy’s says an API plant in India is unlikely to be subject to further regulatory

enforcement after receiving a US FDA 483 with nine observations.

The Srikakulam facility in the Andhra Pradesh region of India was inspected by the US Food

and Drug Administration (FDA) last week resulting in a Form 483 with nine observations, Shilpi

Lathia – a company spokesperson – told in-Pharmatechnologist.com

“The observations were largely related to procedural and other compliances of the plant

system,” she explained. As such “there is no implication on manufacturing and at this stage

production continues as normal,” she added.

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When asked what Dr Reddy‘s Laboratories is doing to fix the issues, Lathia told us it is currently

responding to the agency with its remediation plans and the firm is “confident it won’t lead to

any further enforcement” such as a Warning Letter or import alert.

The plant manufactures bulk active pharmaceutical ingredients (APIs) - including bromfenacna,

celecoxib, ibuprofen, ketorolac tromethamine, naproxen, naproxen sodium, glimepirid,

linagliptin, liraglutide, and nateglinide - used in Dr Reddy‘s finished formulated drugs for export

to the US and EU.

This is not the first time Dr Reddy‘s has fallen foul with the US. In August the US Government‘s

Consumer Product Safety Commission accused the firm of having violated childproof packaging

rules, while an inspection of an API plant in Mexico in 2010 was followed up with an FDA

warning letter banning imports from the site.

Source: http://www.in-pharmatechnologist.com/

MHRA - Department of Health triennial review of arm’s length bodies

The Department of Health (DH) reviews its arm‘s length bodies once every 3 years. This review is looking at what MHRA, the British Pharmacopeia and the Commission on Human Medicines do and how. DH has sent out a public call for evidence to support the reviews. British Pharmacopoeia Commission: triennial review (external link) Commission on Human Medicines: triennial review (external link) MHRA: triennial review (external link)

Source: http://www.mhra.gov.uk/NewsCentre/CON480101

Therapeutic Goods Administration (TGA) publishes business plan 2014-2015

The TGA Business Plan 2014-2015 provides an overview of the organisation's strategic

considerations including our:

mission

key roles and responsibilities

priorities, and our approach to these

areas of particular emphasis

significant changes and challenges.

Mission

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As part of the Department of Health the TGA safeguards and enhances the health of the Australian community through the effective and timely administration of the Therapeutic Goods Act 1989.

Priorities for 2014-15 Our priorities for the next 12 months comprise:

Continuing to regulate therapeutic goods for safety, effectiveness/performance and quality International regulatory convergence and work sharing Continuing a program of quality improvement in regulatory processes and reform in key areas, according to government priorities.

For more details browse: https://www.tga.gov.au/book/export/html/283511

Government plans to make quality accreditation mandatory for new clinical trials

NEW DELHI: Starting early next year, the government is planning to make quality accreditation mandatory for new clinical trials in the country.

"Pharma companies or sponsors keen to conduct new clinical trials in India would have to seek accreditation from the Quality Council of India (QCI) for their sites, ethics committee and

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investigators before they apply for the drug regulator's clearance," said a government official aware of the proposal. For ongoing trials, it may not be made mandatory immediately but these will also be brought under the accreditation fold eventually, he confirmed. This proposal, initiated by the health ministry, is in the works and could be implemented as soon as next month, the official added.

Currently, National Accreditation Board for Hospitals & Healthcare Providers (NABH), an arm

of QCI that offers quality certification to hospitals, clinics, blood banks, wellness centres, and

dental clinics, is firming up standards that trials sites, ethics committees and doctors conducting

such programmes need to maintain to get accreditation. However, the services of NABH have

remained voluntary in nature in the past.

Clinical research in India has been in the eye of a storm in the last three years with public health activists accusing pharma companies and other stakeholders in the sector — contract research organizations (CROs), doctors conducting trials, ethics panels— of not sticking to global best practices and exploiting uninformed patients while testing experimental drugs.

They have accused pharma companies of skimping on compensation to trial victims in case of death and injuries, doctors of not taking proper informed consent of trial volunteers and the government of lax regulation in the space. The pharma companies argue that blaming the entire industry for wrongs committed by a few is not only unfair but also counterproductive for new drug research. The Supreme Court is currently hearing a public interest litigation on the matter.

"We wanted an independent third party to audit and certify the quality standards of trial sites, ethics panels and of doctors undertaking trials if they qualify. That is the reason we approached QCI to take up that responsibility," another government official said.

Of the 10 lakh trials conducted globally, India is home to only 15,000, estimates an expert panel headed by Ranjit Roy Chaudhury. This panel had also recommended accreditation of sites, investigators and ethics committees but by a central accreditation council, the constitution of which it had proposed. Industry experts said this demand will be a tall order till such time NABH is not staffed with specialised experts to carry out such technical audits.

"It is a well thought out plan but will be time consuming and demand substantial resource investment. While thrashing out the modalities, all stakeholders should be consulted to make it feasible," said Saurendra Das, executive director of Excel Life Sciences, a US-headquartered clinical site management firm.

Another CRO said it will be particularly onerous for standalone clinics and small hospital set-ups and new hospitals that are not already conducting trials.

" An audit can certify a trial site only if it has already conducted one or is conducting one but what about those sites which want to start but have no past record?" he said.

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Health Canada publishes International Harmonized Requirements for Batch Certification

Content of the Fabricator's/Manufacturer's Batch Certificate for Drug/Medicinal Products

(Content of the Batch Certificate for Medicinal Products) Exported to Countries under the

Scope of a Mutual Recognition Agreement (MRA)

Explanatory Note

In the framework of Mutual Recognition Agreements (MRA), the Sectoral Annex on Good Manufacturing Practices (GMP) requires a batch certification scheme for medicinal products covered by the pharmaceutical Annex. The internationally harmonized requirements for the content of the batch certificate of a medicinal product are provided in this document.

Each batch of medicinal product transferred between countries having appropriate arrangements on GMP, must be accompanied by a batch certificate issued by the manufacturer in the exporting country. In the framework of MRAs all manufacturing sites must be located in the country issuing the certificate or in another MRA country, if reciprocal arrangements are in force.

This certificate will be issued further to a full qualitative and quantitative analysis of all active and other relevant constituents to ensure that the quality of the products complies with the requirements of the marketing authorisation of the importing country. The batch certificate will attest that the batch meets the specifications and has been manufactured in accordance with the marketing authorisation of the importing country, detailing the specifications of the product, the analytical methods referenced, the analytical results obtained, and containing a statement that the batch processing, packaging and quality control records were reviewed and found in conformity with GMP. The batch certificate will be signed by the person responsible for certifying that the batch is suitable for release for sale or supply/export at the manufacturing site.

The importer of the batch of medicinal product is to receive and maintain the batch certificate issued by the manufacturer. It has to be available to regulatory authorities of the importing country. This certification by the manufacturer on the conformity of each batch is essential to exempt the importer from re-testing.

Where applicable this batch certificate shall also be used for non-finished medicinal products such as intermediates, bulk or partially packed products.

This certificate may also be used for investigational medicinal products used in clinical trial authorisations.

These harmonized requirements have been agreed bilaterally by Canada with the regulatory authorities of the following countries: Australia, countries of the European Economic Area - European Free Trade Association (EEA-EFTA), Member States of the European Union (EU) and Switzerland.

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Content of the Batch Certificate for Medicinal Products

[ LETTER HEAD OF EXPORTING MANUFACTURER ]

1. Name of product

2. Importing country

3. Marketing authorisation number or Clinical Trial Authorisation Number

4. Strength/Potency

5. Dosage form

6. Package size and type

7. Batch number

8. Date of manufacture

9. Expiry date

10. Name, address and authorisation number of all manufacturing sites and quality control

sites

11. Certificates of GMP Compliance of all sites listed under 10 or, if available, EudraGMP

reference numbers

12. Results of analysis

13. Comments/remarks

14. Certification statement

15. Name and position/title of person authorising the batch release

16. Signature of person authorising the batch release

17. Date of signature

Explanatory Notes and Glossary

1. Name of product

Proprietary, brand, trade or proper name in the importing country, as applicable. For

Investigational Medicinal Products (IMPs) the code number as referred to in the clinical

trial application.

2. Importing Country

3. Marketing Authorisation Number or Clinical Trial Authorisation Number

The marketing authorisation number of the product in the importing country. For IMPs,

the Clinical Trial authorisation number or trial reference to be provided when available.

4. Strength/Potency

Identity (name) and amount per unit dose required for all active

ingredients/constituents.IMPs include placebos and the manner in which this information

is provided should not unblind the study.

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5. Dosage form or pharmaceutical form, e.g. tablets, capsules, ointments

6. Package size and type

This would be the contents of container and vials, bottles, blisters, etc.

7. Batch number

or Lot number related to the product. Unique combination of numbers, letters or symbols

that identifies a batch and from which the production and distribution history can be

determined.

8. Date of manufacture

In accordance with national (local) requirements of the importing country.

9. Expiry date

The date placed on the container/label of a product designating the time during which the

product is expected to remain within the authorised shelf life specifications authorised by

the importing country, if stored under defined conditions, and after which it should not be

used.

10. Name, address and authorisation number of all manufacturing and quality control

sites

All sites involved in the manufacture including packaging/labelling and quality control of

the batch should be listed with name, address and authorisation number. The name and

address must correspond to the information provided on the manufacturing authorisation.

11. Certificates of GMP Compliance of all sites listed under 10 or, if available, EudraGMP

reference numbers

Certificate numbers and/or EudraGMP reference numbers should be listed under this

item.

12. Results of analysis

Should include the authorised specifications, all results obtained and refer to the

methods used (may refer to a separate certificate of analysis which must be dated,

signed and attached).

13. Comments/remarks

Any additional information that can be of value to the importer and/or inspector verifying

the compliance of the batch certificate (e.g. specific storage or transportation conditions).

14. Certification statement

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This statement should cover the fabrication/manufacturing, including packaging/labelling

and quality control. The following text should be used: "I hereby certify that the above

information is authentic and accurate. This batch of product has been manufactured,

including packaging/labelling and quality control at the above mentioned site(s) in full

compliance with the GMP requirements of the local Regulatory Authority and with the

specifications in the Marketing Authorisation of the importing country or product

specification file for Investigational Medicinal Products. The batch processing, packaging

and analysis records were reviewed and found to be in compliance with GMP".

15. Name and position/title of person authorising the batch release

Including the name and address, if more than one site is mentioned under item 10.

16. Signature of person authorising the batch release

17. Date of signature

Glossary of equivalent terms used in the Certificate template (non-exhaustive)

batch = lot

dosage form = pharmaceutical form

manufacturer = fabricator

manufacturing/manufacture = fabrication

manufacturing authorisation = establishment licence

medicinal product = pharmaceutical product = drug product

quality control = testing

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The Top 15 Pharmaceutical Deficiencies Cited by FDA in 2014

The US Food and Drug Administration (FDA) has released data on the observations it makes during inspections of pharmaceutical facilities, indicating the most common issues faced by pharmaceutical companies.

Total 483s Issued Declines for First Time in Six Years

In its most recent report, FY 2014 Inspectional Observation Summaries, FDA said it issued 645 Form 483s—forms indicating areas of noncompliance at a facility—to pharmaceutical companies in fiscal year 2014.

The number of 473s issued (645) marked the second consecutive year FDA has issued fewer pharmaceutical 483s than the year prior, and the 2014 total (645) is 19% less than its 2012 high water mark (787 inspections).

FDA's inspections also noted common deficiencies by pharmaceutical manufacturers.

Regulatory Citation

Short Description Long Description Frequen

cy

21 CFR 211.22(d)

Procedures not in writing, fully followed

The responsibilities and procedures applicable to the quality control unit are not [in writing] [fully followed].

145

21 CFR 211.160(b)

Scientifically sound laboratory controls

Laboratory controls do not include the establishment of scientifically sound and appropriate [specifications] [standards] [sampling plans] [test procedures] designed to assure that [components] [drug product containers] [closures] [in-process materials] [labeling] [drug products] conform to

109

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appropriate standards of identity, strength, quality and purity.

21 CFR 211.192

Investigations of discrepancies, failures

There is a failure to thoroughly review [any unexplained discrepancy] [the failure of a batch or any of its components to meet any of its specifications] whether or not the batch has been already distributed.

94

21 CFR 211.100(a)

Absence of Written Procedures

There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.

87

21 CFR 211.67(b)

Written procedures not established/followed

Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product.

72

21 CFR 211.113(b)

Procedures for sterile drug products

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not [established] [written] [followed].

72

21 CFR 211.165(a)

Testing and release for distribution

Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the [final specifications] [identity and strength of each active ingredient] prior to release.

64

21 CFR 211.67(a)

Cleaning / Sanitizing / Maintenance

Equipment and utensils are not [cleaned] [maintained] [sanitized] at appropriate intervals to prevent [malfunctions] [contamination] that would alter the safety, identity, strength, quality or purity of the drug product.

63

21 CFR 211.68(a)

Calibration/Inspection/Checking not done

Routine [calibration] [inspection] [checking] of [automatic] [mechanical] [electronic] equipment is not performed according to a written program designed to assure proper performance.

54

21 CFR 211.166(a)

Lack of written stability program

There is no written testing program designed to assess the stability characteristics of drug products.

51

21 CFR 211.110(a)

Control procedures to monitor and validate performance

Control procedures are not established which [monitor the output] [validate the performance] of those manufacturing processes that may be responsible for

51

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causing variability in the characteristics of in-process material and the drug product. "

21 CFR 211.198(a)

Complaint Handling Procedure

Procedures describing the handling of written and oral complaints related to drug products are [not written or followed] [deficiently written or followed].

47

21 CFR 211.25(a)

Training--operations, GMPs, written procedures

Employees are not given training in [the particular operations they perform as part of their function] [current good manufacturing practices] [written procedures required by current good manufacturing practice regulations].

46

21 CFR 211.100(b)

SOPs not followed / documented

Written production and process control procedures are not [followed in the execution of production and process control functions] [documented at the time of performance].

43

21 CFR 211.188

Prepared for each batch, include complete information

Batch production and control records [are not prepared for each batch of drug product produced] [do not include complete information relating to the production and control of each batch].

43

Source: http://www.raps.org/

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The 11 biggest drug launches to watch in 2015

This past year was a milestone one in the United States for new drugs, with novel therapeutics

such as Gilead's pricey hep C cures Sovaldi and Harvoni coming to market (as well as a record

15 approvals for drugs to treat rare diseases), and huge sales of newer drugs like Roche's

breast cancer med Kadcyla and Biogen Idec's MS blockbuster Tecfidera.

But according to a new report by EvaluatePharma (gated), 2015 could be equally impressive in

terms of drug launches as innovative candidates in massive medical markets and exciting new

drug classes in cancer immuno-therapy work their way towards approval.

"The value of 2015 launches will be helped along by penetration into massive yet already well-

trodden sectors like cardiovascular and respiratory disease, along with diabetes and

schizophrenia," wrote the authors. "Drugs treating high cholesterol and heart failure are set to

dominate the year's new products, with combine 2020 sales forecast at $8bn."

"The most keenly awaited launches of the year should come from the competing cholesterol-

lowering drugs alirocumab from Sanofi and evolocumab from Amgen."

EvaluatePharma aggregated equity analysts' expectations for 2015's biggest potential drug

launches, including their predictions for 2015 and 2020 sales. Here are the 11 expected

launches that the industry should be watching next year:

1. Opdivo/nivolumab (Bristol-Myers Squibb)

Company: Bristol-Myers Squibb

Pharmaceutical class/therapeutic area: Cancer/anti-PD-1 monoclonal antibody

Current regulatory status: Filed for approval in U.S., EU

Anticipated 2015 sales: $658 million

Anticipated 2020 sales: $7.122 billion

What to watch: Opdivo is projected to be the biggest new drug launch in the U.S. and one of the

biggest launches worldwide this decade. It became the first approved anti-PD-1 medication

when it was cleared in Japan and has shown promise in treating Hodgkin's lymphoma on top of

multiple myeloma (and is being tested on many other cancers). But the really good news for

BMS is that Opdivo has produced a better response rate in trials than Merck's competing (and

historic) PD-1 inhibitor Keytruda (pembrolizumab). If that trend continues, then BMS could rule

this exciting new therapeutic class. The FDA is expected to decide on Opdivo approval by

March.

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2. Alirocumab (Sanofi/Regeneron)

Company: Sanofi/Regeneron

Pharmaceutical class/therapeutic area: LDL cholesterol reducer/anti-PCSK9 monoclonal

antibody

Current regulatory status: Phase III trials

Anticipated 2015 sales: $44 million

Anticipated 2020 sales: $2.179 billion

What to watch: PCSK9 inhibitors, besides anti-PD-1 drugs, are the most exciting new

therapeutic class to come out of the woodwork in recent times. What makes these LDL-lowering

drugs particularly exciting is the timing of their filings, with doctors' groups in the U.S. and EU

having recently endorsed controversial new guidelines that significantly expand the use of

statins. If that course of action proves too risky, and PCSK9 drugs like alirocumab aren't

prohibitively pricey, these could become the go-to option in an absolutely critical field.

3. Evolocumab (Amgen/Astellas)

Company: Amgen/Astellas

Pharmaceutical class/therapeutic area: LDL cholesterol reducer/anti-PCSK9 monoclonal

antibody

Current regulatory status: Filed for approval

Anticipated 2015 sales: $77 million

Anticipated 2020 sales: $1.947 billion

4. Toujeo (Sanofi)

Company: Sanofi

Pharmaceutical class/therapeutic area: Diabetes (long-acting insulin)

Current regulatory status: Filed for approval

Anticipated 2015 sales: $139 million

Anticipated 2020 sales: $1.692 billion

What to watch: You can bet that Sanofi execs will be looking closely at how well Toujeo, the

company's successor to the flagship (but now fading) long-acting insulin Lantus, performs in the

market as the company struggles with a flagging diabetes franchise. What's really giving Sanofi

heartburn is the prospect of competition from Eli Lilly's Lantus biosimilar, which is being

marketed as Abasria in the EU. The goal? $1.7 billion in sales in 2020.

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5. Mepolizumab (GlaxoSmithKline)

Company: GlaxoSmithKline

Pharmaceutical class/therapeutic area: Severe asthma/anti-IL-5 monoclonal antibody

Current regulatory status: Filed for approval

Anticipated 2015 sales: $28 million

Anticipated 2020 sales: $1.161 billion

6. Cosentyx (Novartis)

Company: Novartis

Pharmaceutical class/therapeutic area: Psoriasis/anti-IL-17A monoclonal antibody

Current regulatory status: Filed for approval

Anticipated 2015 sales: $133 million

Anticipated 2020 sales: $1.099 billion

7. VX-809 + Kalydeco/ivacaftor (Vertex Pharmaceuticals)

Company: Vertex Pharmaceuticals

Pharmaceutical class/therapeutic area: Cystic fibrosis/CFTR corrector

Current regulatory status: Filed for approval

Anticipated 2015 sales: $575 million

Anticipated 2020 sales: $4.744 billion

8. LCZ696 (Novartis)

Company: Novartis

Pharmaceutical class/therapeutic area: Heart failure/AT1 & ARNI

Current regulatory status: Phase III trials

Anticipated 2015 sales: $251 million

Anticipated 2020 sales: $3.875 billion

What to watch: This one will be huge. If approved (once Novartis moves ahead and files the

drug), LCZ696 will be the first new drug launch with a hospitalization/death prevention in heart

failure patients indication in years. It has been granted the EU's version of priority review status.

9. Palbociclib (Pfizer)

Company: Pfizer

Pharmaceutical class/therapeutic area: Breast cancer/CDK 4 & 6 inhibitor

Current regulatory status: Filed for approval

Anticipated 2015 sales: $281 million

Anticipated 2020 sales: $3.078 billion

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10. Selexipag (Actelion)

Company: Actelion

Pharmaceutical class/therapeutic area: Pulmonary arterial hypertension (PAH)/prostacyclin

agonist

Current regulatory status: Phase III trials

Anticipated 2015 sales: $18 million

Anticipated 2020 sales: $1.245 billion

What to watch: Selexipag has the advantage over Glaxo's mepolizumab in terms of respiratory

launches, according to the EvaluatePharma researchers. As the report authors note, payers will

likely be reticent to prescribe a lung biologic to a large host of patients.

11. Brexpiprazole (Otsuka Holdings)

Company: Otsuka Holdings

Pharmaceutical class/therapeutic area: Schizophrenia/5-HT1A & D2 & 5-HT2

Current regulatory status: Filed for approval

Anticipated 2015 sales: $95 million

Anticipated 2020 sales: $1.141 billion

What to watch: This could be a game-changer in a field that hasn't seen too many of them in

recent years. The FDA is currently reviewing an NDA for the drug as a first-line schizophrenia

treatment and a secondary therapy for major depression. It would also be a natural successor

to Otsuka's antipsychotic Abilify, whose sales slid to $1.03 million in Q1 2014.

IPC initiates work on Addendum 2016 & 53 monographs already identified by experts

After the launch of IP Addendum-2015 to IP-2014, the Indian Pharmacopoeia Commission

(IPC) has already started the work on Addendum 2016. For this, a list of 53 monographs has

already been identified by the experts for phase I drafting, which are approved by CDSCO

along with 13 monographs provided by the stakeholders.

Out of these, 17 monographs are already drafted awaiting comments from the stakeholders.

Sources inform that this Addendum will also have monographs that were not included in IP-

2014 and its Addendum-2015, but are in the compiled list of monographs that are CDSCO

approved, available in NLEM and accepted in market.

Interestingly, as a breather for many, formulations whose API monographs were not included in

IP-2014 and in it‘s Addendum-2015 may also be considered to be included in this. This is along

with the monographs proposed by the stakeholders as deemed fit by the IPC.

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It is understood that the experts will take important decision regarding the new addendum and

erratas, in a three-day working committee meeting, which started off in IPC Ghaziabad on

December 15. Erratas basically deals with monographs and appendices in IP 2014 and

addendum 2015 that needed corrections based on scientific in-puts.

Dr Raman Mohan Singh, principal scientific officer, quality manager and coordinator, Indian

Pharmacopoeia Laboratory, IPC informed that they have already issued erratas 001 and 002 to

IP 2014 in October itself by Dr G N Singh the secretary-cum-scientific director of IPC, for

immediate compliance of the stakeholders. He said that this meeting would further discuss

about details to be included in erratas 003.

―IPC is committed towards its aim to ensure availability of only the best and highest quality of

medicines in the country. It is in continuation with this, we have decided to not only keep on

upgrading the already existent monographs but also adding new to our list,‖ Dr Singh added.

IPC has already completed the preparation of list of new monographs and revised tests for the

new Addendum, while work is going on to acquire and verify new monographs, expected to be

completed by end of December 2014. Dr Raman Singh informs that, if things go as planned,

IPC plan to release the Addendum by September 2015 for its expected implementation in

January 2016.

Frequent GMP Question: How many Signatures are required for Validation Protocols/

Reports?

As part of the validation and qualification activities for the production of medicinal products, the

following question often arises: how many signatures have to be put under the respective

protocols and reports? What is the responsibility of the Head of Production and the QA

department in this matter?

Indications can be found in the chapters 1, 2 and 4 of the EU GMP Guide Part I. You can find in

Chapter 4 requirements on the topic "Documentation":

4.2. "Documents should be designed, prepared, reviewed, and distributed with care."

4.3. "Documents containing instructions should be approved, signed and dated by appropriate

and authorised persons."

This can be summarized as follows: each document should have one author, one reviewer and

one approver. The Head of Production is responsible for the qualification of his equipment and

the validation of his processes (Chapter 2.7 (4)); the same applies to the Head of QC in the lab

(2.8.).

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Since the introduction of the revised Chapter 2 in February this year, a new point has been

added. Moreover - depending on the size and the organisational structure of the company - an

independent Head of Quality Assurance or Quality Unit can be assigned. Where such a function

exists usually some of the responsibilities described in 2.6, 2.7 and 2.8 are shared with the

Head of Quality Control and Head of Production. Senior management should therefore take

care that roles, responsibilities, and authorities are defined. This means for example that the

QA can assume the tasks of the Head of Production. Basically, the QM system should ensure

that validation is performed (1.4 (10)).

Conclusion: Depending on your internal structure, you can specify the signature rules. You

should be aware of what "approved" and "released" mean as both can have various meanings.

"Approved" can be used for a document, for a technical review, for execution, or can even have

a completely different meaning in conjunction with other terms. Similarly, depending on the term

you use in combination with "released" its meaning is different, as, i.e., released formally or

textually. Some companies set such definitions in a SOP documentation.

Finally, the GMP Guide gives the freedom to do it otherwise; if you - at least - come to the same

conclusion and can prove it.

In the US, the procedure is slightly different. There, the personal responsibility of the Head of

Production / QC is not part of the GMP regulation. On the contrary, it is the QCU who has a

crucial role.

The American Society of Testing and Materials (ASTM) has a quite different

approach. The document ASTM E 2500 defines "Subject Matter Experts" for qualification.

According to this model, the QA department would only sign superordinate qualification

documents. This is an interesting and lean approach although not very common Europe yet.

Health products quarantined from two sites in India as Health Canada assesses data

integrity concerns

Starting date: December 23, 2014

Type of communication: Information Update

Subcategory: Drugs

Source of recall: Health Canada

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Issue: Improper Safety Mechanisms, Suspected quality concern, Product Safety, Quality

Audience: General Public

Identification number: RA-43061

Issue

At Health Canada's request, Canadian importers have agreed to quarantine health products from the following two India-based sites due to data integrity concerns:

Dr. Reddy's Laboratories in Srikakulam, India

IPCA Laboratories in Pithampur, India

This action comes in light of recent information from a trusted regulatory partner that raises concerns about the reliability of the laboratory data generated at these sites. Health Canada is taking this action as an interim precautionary measure to help mitigate any potential risk.

A quarantine means that the Canadian importers have agreed to stop the importation and distribution of products from these two sites. At this time there is no identified risk to health, and Health Canada is not requesting a recall of any of the products.

Health Canada's action applies to active pharmaceutical ingredients (APIs) from Dr. Reddy's Laboratories as well as to finished drug products from a different IPCA Laboratories facility than is currently subject to import restrictions by Health Canada. Health Canada has compiled an initial list of products affected by the quarantine. The list will be updated as new information becomes available. To date, none of the affected products have been determined by Health Canada to be medically necessary.

Health Canada will continue to work with international partners and Canadian importers to gather and assess information regarding the situation and take action as necessary to help protect Canadians.

Canadians should not make any changes to their medication without first consulting with a healthcare professional.

Health Canada has also engaged provinces and territories to share information about the situation and will continue to collaborate. The Department will continue to keep Canadians informed as new information becomes available.

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FDA Making Changes to Drug and Manufacturing Oversight

FDA Commissioner Margaret Hamburg, MD, is seeking new ways for the agency to deal with its

complex regulatory roles, especially as it pertains to drugs.

In 2013, Hamburg came up with a new agency wide organization to make key

recommendations to improve how FDA centers deal with its audit employees. The result of that

effort is the new Program Alignment Group Plan that will integrate the centers and field

oversight operations.

CDER also is enacting a large reorganization that is made to improve old quality programs and

to better ensure drug quality. The director of CDER, Janet Woodcock, is setting up a new Office

of Pharmaceutical Quality or OPQ. The idea is to provide a single voice for drug quality that will

coordinate research, review and audit duties as they pertain to quality.

The inspection functions done by the Office of Regulatory Affairs are being revised. For drugs,

one of the big efforts will be to enact a pharmaceutical inspectorate with specialized expets that

will both inspect and evaluate manufacturing processes for drugs. CDER staff is going to work

in certain CGMP audits more and will give additional input into the scheduling of inspections, as

well as enforcement.

Also up for overhaul is the manufacture registration and inventory databases. This will

harmonize all center and data systems at ORA. This will use facility IDs that are most common,

codes for products and modern software platforms that allow everyone to access data of

facilities, AERs, risk info and field inventory.

The reorganization of CDER will go live in early 2016, and will shift most functions of the Office

of Pharmaceutical Science over to OPQ. OPQ is then going to evaluate CMC submissions for

pharmaceuticals, biotechnology and generic drugs.

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Calibration:

The set of operations that establish, under specified conditions, the relationship

between values indicated by an instrument or system for measuring (for

example, weight, temperature and pH), recording, and controlling, or the

values represented by a material measure, and the corresponding known

values of a reference standard. Limits for acceptance of the results of

measuring should be established. Always remember any reference standard is

always used in calibration.

Validation:

Action of proving and documenting that any process, procedure or method

actually and consistently leads to the expected results. It can better understand

that the validation is a documented evidence to and done to prove the

consistency of the expected results of any process, procedure or method.

Qualification:

Action of proving and documenting that any premises, systems and equipment

are properly installed, and/or work correctly and lead to the expected results.

Qualification is often a part (the initial stage) of validation, but the individual

qualification steps alone do not constitute process validation. Qualification is a

part of validation.

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New Guidance FDA Draft Guidance for Industry: SUPAC: Manufacturing Equipment Addendum:

This guidance combines and supersedes the following scale-up and post-approval changes

(SUPAC) guidances for industry:

(1) SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral Dosage Forms, Manufacturing Equipment Addendum, and

(2) SUPAC-SS Nonsterile Semisolid Dosage Forms, Manufacturing Equipment Addendum.

It removes the lists of manufacturing equipment that were in both guidances and clarifies the

types of processes being referenced.

Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid

ances/UCM346049.pdf

FDA Draft Guidance for Industry: DSCSA Standards for the Interoperable Exchange of

Information for Tracing of Certain Human, Finished, Prescription Drugs: How to

Exchange Product Tracing Information

This guidance addresses the pharmaceutical security provisions in section 582 of the Federal

Food, Drug, and Cosmetic Act (FD&C Act). Section 582 was added by the Drug Supply Chain

Security Act (DSCSA) (Title II of Public Law 113-54) and facilitates the tracing of products

through the pharmaceutical distribution supply chain by requiring certain trading partners

(manufacturers, repackagers, wholesale distributors, and dispensers) to exchange transaction

information, transaction history, and a transaction statement (product tracing information) when

engaging in transactions involving certain prescription drugs.3 25 This requirement goes into

effect on January 1, 2015, for manufacturers, repackagers, and wholesale distributors, and on

July 1, 2015, for dispensers. FDA, in consultation with other appropriate Federal officials and

pharmaceutical distribution supply chain stakeholders, is required, under section 582(a)(2)(A) of

the FD&C Act, to establish initial standards for the interoperable exchange of the product

tracing information related to each transaction of certain human, finished, prescription drugs

covered by the statute.

Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid

ances/UCM424895.pdf

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FDA Draft Guidance for Industry:Recommended Warning for Over-the-Counter

Acetaminophen-Containing Drug Products and Labeling Statements Regarding Serious

Skin Reactions

FDA is informing manufacturers, members of the medical and scientific community, and other

interested persons that at this time we do not intend to object to the marketing of single- and

combination-ingredient, acetaminophen-containing, nonprescription (commonly referred to as

over-the-counter (OTC)) drug products bearing a warning as described in this guidance (see

section III, Discussion and Policy) alerting consumers that the use of acetaminophen may

cause severe skin reactions. This guidance is intended to apply to single- and combination-

ingredient acetaminophen-containing products marketed under the Tentative Final Monograph

(TFM) for Internal Analgesic, Antipyretic, and Antirheumatic (IAAA) Drug Products for Over-the-

Counter Human Use, published in the Federal Register (53 FR 46204, November 16, 1988).

Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid

ances/UCM424898.pdf

FDA Draft Guidance for Industry: How to Obtain a Letter from FDA Stating that

Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable

REMS for RLD

This guidance describes how a prospective abbreviated new drug application (ANDA) applicant

may request a letter stating that FDA has determined: (1) that the prospective applicant‘s

bioequivalence (BE) study protocol contains safety protections comparable to those in the risk

evaluation and mitigation strategy (REMS) with elements to assure safe use (ETASU)

applicable to the reference listed drug (RLD), and (2) that FDA will not consider it a violation of

the REMS for the RLD sponsor to provide a sufficient quantity of the RLD to the interested

generic firm or its agent to allow the firm to perform the testing necessary to support its ANDA.

Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid

ances/UCM425662.pdf

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Guidance for Industry: Pregnancy, Lactation, and Reproductive Potential: Labeling for

Human Prescription Drug and Biological Products — Content and Format

This guidance is intended to assist applicants in complying with new content and format

requirements of the Pregnancy, Lactation, and Females and Males of Reproductive Potential

subsections of labeling for human prescription drug and biological products (as described in the

final rule published concurrently with this draft guidance). The guidance provides information for

preparing subsections 8.1 Pregnancy, 8.2 Lactation, and 8.3 Females and Males of

Reproductive Potential of the USE IN SPECIFIC POPULATIONS section of the full prescribing

information (FPI) described in 21 CFR 201.56(d)(1) and 201.57(c)(9)(i) through (iii).

Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid

ances/UCM425398.pdf

Pregnancy and Lactation Labeling Final Rule

The FDA published the Content and Format of Labeling for Human Prescription Drug and

Biological Products; Requirements for Pregnancy and Lactation Labeling, referred to as the

―Pregnancy and Lactation Labeling Rule‖ (PLLR or final rule).

The PLLR requires changes to the content and format for information presented in prescription

drug labeling in the Physician Labeling Rule (PLR) format to assist health care providers in

assessing benefit versus risk and in subsequent counseling of pregnant women and nursing

mothers who need to take medication, thus allowing them to make informed and educated

decisions for themselves and their children. The PLLR removes pregnancy letter categories –

A, B, C, D and X. The PLLR also requires the label to be updated when information becomes

outdated.

Below is a comparison of the current prescription drug labeling with the new PLLR labeling

requirements.

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The Pregnancy subsection (8.1) includes information for a pregnancy exposure registry for the

drug when one is available. Pregnancy exposure registries collect and maintain data on the

effects of approved drugs that are prescribed to and used by pregnant women. Information

about the existence of any pregnancy registries in drug labeling has been recommended but

not required until now. Information in the Pregnancy sub-section includes a Risk Summary,

Clinical considerations, and Data. Information formerly found in the ―Labor and delivery‖

subsection is now included in the ―Pregnancy‖ subsection.

The Nursing mothers subsection was renamed, the Lactation subsection (8.2), and provides

information about using the drug while breastfeeding, such as the amount of drug in breast milk

and potential effects on the breastfed infant.

The Females and Males of Reproductive Potential subsection (8.3), new to the labeling,

includes information, when necessary, about the need for pregnancy testing, contraception

recommendations, and information about infertility as it relates to the drug.

The labeling changes go into effect on June 30, 2015. Prescription drugs and biologic

products submitted after June 30, 2015, will use the new format immediately, while labeling for

prescription drugs approved on or after June 30, 2001, will be phased in gradually.

Labeling for over-the-counter (OTC) medicines will not change; OTC drug products are not

affected by the final rule.

Concurrently with publishing the PLLR, FDA also issued draft guidance for industry to assist

drug manufacturers in complying with the new labeling content and format requirements. Source: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Label

ing/ucm093307.ht

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Draft questions and answers on cyclodextrins in the context of the revision of the

guideline on ‘Excipients in the label and package leaflet of medicinal products for human

use'

Following the European Commission decision to revise the Annex of the guideline on

‗Excipients in the label and package leaflet of medicinal products for human use‘ (CPMP/463/00

Rev. 1), a multidisciplinary group of experts was created in 2011 to update the labelling of

selected excipients listed in the annex of the guideline and to add new excipients to the list,

based on a review of their safety. Draft Q&A documents on excipients are progressively

released for public consultation. They include proposals for new or updated information for the

labelling and package leaflet. A corresponding background report supporting the review is

published for information only.

Source: http://www.ema.europa.eu/ema/doc_index.jsp?curl=pages/includes/document/docume

nt_detail.jsp?webContentId=WC500177944&murl=menus/document_library/document_library.j

sp&mid=0b01ac058009a3dc

Draft questions and answers on propylene glycol and esters in the context of the

revision of the guideline on ‘Excipients in the label and package leaflet of medicinal

products for human use’

Following the European Commission decision to revise the Annex of the guideline on

‗Excipients in the label and package leaflet of medicinal products for human use‘ (CPMP/463/00

Rev. 1), a multidisciplinary group of experts was created in 2011 to update the labelling of

selected excipients listed in the annex of the guideline and to add new excipients to the list,

based on a review of their safety. Draft Q&A documents on excipients are progressively

released for public consultation. They include proposals for new or updated information for the

labelling and package leaflet. A corresponding background report supporting the review is

published for information only.

Source: http://www.ema.europa.eu/ema/doc_index.jsp?curl=pages/includes/document/docume

nt_detail.jsp?webContentId=WC500177945&murl=menus/document_library/document_library.j

sp&mid=0b01ac058009a3dc

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General Chapter <800> Hazardous Drugs—Handling in Healthcare Settings

Type of Posting : Notice of Intent to Revise

Posting Date: 13–Oct–2014; updated 01–Dec–2014

Targeted Official Date: TBD

Expert Committee: Compounding

In accordance with section 7.05(c) of the 2010–2015 Rules and Procedures of the Council of

Experts, this is to provide notice that the Compounding Expert Committee intends to republish

General Chapter <800> Hazardous Drugs—Handling in Healthcare Settings in the

Pharmacopeial Forum (PF). The General Chapter, which was originally published in PF 40(3)

[May–Jun. 2014], provides standards to protect personnel and the environment when handling

hazardous drugs.

The Compounding Expert Committee is republishing General Chapter <800> in PF 41(2) [Mar.–

Apr. 2015] due to the nature and significance of the comments received on the original PF

proposal. The revision clarifies wording and reflects new and revised guidance documents and

stakeholder input.

General Chapter <800> is being presented in advance of its publication in PF 41(2) to allow

additional time for public review and comment. To ensure that all comments are addressed,

please indicate the line number(s) corresponding to your comments and submit

toCompoundingSL@usp.org. The General Chapter is available with line numbers at the link

below. Comments will be accepted until May 31, 2015.

Proposed Revisions to the General Notices and Requirements to be Published for

Comment in Pharmacopeial Forum 41(1) [Jan.–Feb. 2015]

Type of Posting: General Announcement

Posting Date: 05–Dec–2014

Targeted Official Date: 01–May–2016

Expert Committee: Council of Experts Executive Committee

To provide additional time for review and input, USP is posting in advance the proposed

General Notices and Requirements (GN) section of the United States Pharmacopeia and the

National Formulary (USP–NF) that will be published for public notice and comment in

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Pharmacopeial Forum 41(1) [Jan.–Feb. 2015]. GN is regularly revised to refine and clarify its

content. GN was most recently revised in the Second Supplement to USP 37–NF 32 (published

June 1, 2014; official December 1, 2014). This current proposal has been informed by input

from stakeholders on the General Notices Project Team, representatives of the U.S. Food and

Drug Administration, and members of the Council of Experts Executive Committee, who

discussed these revisions in their September 16–17, 2014 meeting. The following links provide

access to both a summary of changes that are proposed for this round of GN revisions and to

the GN file itself.

ICH Releases Three New Guidance Documents

Questions & Answers: Selection and Justification of Starting Materials for the

Manufacture of Drug Substances This Implementation Working Group (IWG) was endorsed by the ICH Steering Committee

in November 2014.

Experience gained with the implementation of the ICH Q11 Guideline since its finalisation

in 2012 shows that some clarification is needed on what information about the selection

and justification of starting materials should be provided in marketing authorization

applications and/or Master Files.

The Q11 IWG is tasked to develop a Questions and Answers (Q&A) document which will

be focusing on chemical entity drug substances as that is where most of the differences of

opinion have been experienced.

Implementation of Guideline for Elemental Impurities This Implementation Working Group (IWG) was endorsed by the ICH Steering Committee

in October 2014. Throughout the development of the Q3D Guideline, external audiences,

constituents and interested parties have clearly communicated the complexity of the

implementation approaches for this guideline. While the Q11 Guideline provides the

framework, it cannot provide the detailed examples covering the breadth of potential case

studies for products within scope of the guideline. Consequently, the ICH SC considered

that the development of a comprehensive training programme and supporting

documentation sponsored by ICH was necessary to ensure the proper interpretation and

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effective utilisation by industry and regulators alike to enable a harmonised and smooth

implementation of Q3D on a global basis.

Safety single This topic was endorsed by the ICH Steering Committee in November 2014.

The S11 Guideline is proposed to provide direction on the nonclinical safety studies

important to support a pediatric development program. It will recommend standards for the

conditions under which nonclinical juvenile animal testing is considered informative and

necessary to support paediatric clinical trials, and also provide guidance on the design of

the studies. A streamlined drug development and higher scientific rigor while minimizing

the unnecessary use of animals will be achieved with the implementation of this new

harmonised ICH Guideline.

EMA releases Guideline on quality of transdermal patches

This guideline addresses new marketing authorisation applications (including generic or

abridged applications) and subsequent variation submissions for transdermal patches for

systemic delivery.

Guidance is provided on the quality requirements for the description, development,

manufacture, characterisation of excipients, control of drug product, packaging and stability of

transdermal patches. In particular, in vitro performance testing with respect to drug release,

adhesion and skin permeation is discussed, together with its relation to clinical and in vivo

performance.

It should be read in conjunction with the Guideline on the Pharmacokinetic and clinical

evaluation of modified-release dosage forms.

Transdermal patches are designed to provide a controlled delivery of the active substance(s)

through the skin, principally by diffusion, resulting in a defined rate and extent of systemic

delivery of active substance

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FDA issues Guidance for a clear Identification of pharmaceutical Companies

In our GMP News from September 2013 you learned about a draft of a FDA Guidance for

Industry entitled "Specification of the Unique Facility Identifier (UFI) System for Drug

Establishment Registration". This document's goal was to clearly identify pharmaceutical sites.

The draft comprised (manageable) five pages - including the cover page. And in terms of

volume this didn't change. However, some of the alternatives still mentioned in the draft, are not

stated any longer - as one can find out when contacting the authority in these cases. The

method now wanted is a registration by a D-U-N-S- (Data Universal Numbering System)

number. This number - which is a 9-digit code - is supplied by the company Dun & Bradstreet.

Providing Regulatory Submissions In Electronic Format — Standardized Study Data

Under section 745A(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), at least 24

months after the issuance of a final guidance document in which the Food and Drug

Administration (FDA) has specified the electronic format for submitting certain submission types

to the Agency, such content must be submitted electronically and in the format specified by

FDA. This guidance and the technical specifications documents it incorporates by reference

describe the requirements for an electronic submission of standardized clinical and nonclinical

study data under section 745A(a) of the FD&C Act. In accordance with section 745A(a),

following the issuance of a final guidance on this topic, study data contained in the submission

types identified in this guidance must be submitted electronically in a format that FDA can

process, review, and archive.

Providing Regulatory Submissions in Electronic Format — Submissions Under Section

745A(a) of the Federal Food, Drug, and Cosmetic Act

Section 745A(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), added by section

1136 of the Food and Drug Administration Safety and Innovation Act (FDASIA) (Public Law

112-144), requires that submissions under section 505(b), (i), or (j) of the FD&C Act and

submissions under section 351(a) or (k) of the Public Health Service Act (PHS Act) be

submitted in electronic format specified by the Food and Drug Administration (FDA or the

Agency) beginning no earlier than 24 months after FDA issues a final guidance specifying an

electronic submission format.

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Health Canada Draft Guidance - Tamper-Resistant Formulations of Opioid Drug Product

Submissions

This document is intended to provide guidance to sponsors seeking a Notice of Compliance for

their tamper-resistant controlled-release opioid products. It provides information on what

evidence is required to demonstrate tamper-resistance of the product to support a drug

submission under the Food and Drug Regulations.

Opioids are also controlled substances and are, therefore, also subject to the Controlled Drugs

and Substances Act (CDSA) and its regulations. The CDSA and its regulations provide

oversight for the control of substances that can alter mental processes or may cause harm to

individuals and to society when diverted or misused, with the aim of supporting their legitimate

use.

In recent years, the Therapeutic Products Directorate (TPD) has seen a steady increase in the

number of drug submissions received for opioid drugs with tamper-resistant formulations.

These formulations are designed to resist a number of common tampering methods and

potentially provide barriers to certain methods of drug abuse. The abuse of opioids is an

important public health and safety issue. Health Canada, as the federal regulator of

pharmaceuticals, is committed to decreasing the risk of abuse associated with opioid drugs

while ensuring these products remain available to patients. Other controls aimed at reducing

opioid abuse may be imposed by provinces or professional provincial licensing bodies.

This document is intended to provide guidance to sponsors seeking a Notice of Compliance for

their tamper-resistant controlled-release opioid products. It provides information on what

evidence is required to demonstrate tamper-resistance of the product to support a drug

submission under the Food and Drug Regulations.

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AUDIT FINDINGS - 483 Observations

Firm Name 483 Observation

L. Perrigo Co. The reproducibility of test methods have not been established and

documented.

Pfizer Ireland

Pharmaceuticals, Inc.

All records related to the manufacture of intermediates or API were

not adequately reviewed.

Mayo Clinic PET

Radiochemistry

Facility

Periodic reports of non-alert adverse drug experiences have not

been submitted quarterly for an application which was approved less

than three years ago.

3M Drug Delivery

Systems

Appropriate controls are not exercised over computers or related

systems to assure that changes in master production and control

records or other records are instituted only by authorized personnel.

Ishihara Sangyo

Kaisha, Ltd.

Validation of the production process and testing methods used in the

manufacture of ** and ** intended for use as active pharmaceutical

ingredients in ** products have not been demonstrated.

Abraxis Bioscience,

LLC

Laboratory controls do not include a determination of conformance to

written descriptions of sampling procedures for drug products.

Hieber's Pharmacy Procedures designed to prevent microbiological contamination of

drug products purporting to be sterile do not include validation of the

sterilization process.

Brenntag Great

Lakes, LLC

The cleaning procedures for bulk blending tanks ** used to

manufacture OTC drug blends, are not validated.

Abbvie Ltd. Procedures describing the handling of written and oral complaints

related to drug products are not written or followed.

High Chemical

Company

There is a failure to thoroughly review any unexplained discrepancy

and the failure of a batch or any of its components to meet any of its

specifications whether or not the batch has been already distributed.

Lifetech Resources,

LLC

Written procedures are not established and followed for the cleaning

and maintenance of equipment, including utensils, used in the

manufacture, processing, packing or holding of a drug product.

DNA Pharmacy

Services, Inc. dba

Palm Beach

Compounding

There is no written testing program designed to assess the stability

characteristics of drug products.

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483 of Teva Parenteral Medicines Inc (Jul-2009)

QUALITY SYSTEM:

The quality control unit lacks responsibility to approve and reject all procedures or

specifications impacting on the identity, strength, quality, and purity of drug products.

Testing and release of drug product for distribution do not include appropriate laboratory

determination of satisfactory conformance to the final specifications prior to release.

In-process materials are not tested for quality and purity and approved or rejected by the

quality control unit during the production process.

Acceptance criteria for the sampling and testing conducted by the quality control unit is

not adequate to assure that batches of drug products meet appropriate statistical quality

control criteria as a condition for their approval and release.

There is a failure to thoroughly review any unexplained discrepancy whether or not the

batch has been already distributed.

Investigations of an unexplained discrepancy did not extend to other batches of the

same drug product and other drug products that may have been associated with the

specific failure or discrepancy.

The responsibilities and procedures applicable to the quality control unit are not in

writing.

Drug product production and control records, are not reviewed by the quality control unit

to determine compliance with all established, approved written procedures before a

batch is released or distributed.

FACILITIES AND EQUIPMENT SYSTEM:

Equipment used in the manufacture, processing, packing or holding of drug products is

not of appropriate design to facilitate operations for its intended use.

Aseptic processing areas are deficient regarding systems for maintaining any equipment

used to control the aseptic conditions.

Equipment and utensils are not cleaned and sanitized at appropriate intervals to prevent

contamination that would alter the safety, identity, strength, quality or purity of the drug

product.

Records are not kept for the cleaning and sanitizing of equipment.

Aseptic processing areas are deficient regarding the system for monitoring

environmental conditions.

LABORATORY SYSTEM:

Each batch of drug product required to be free of objectionable microorganisms is not

tested through appropriate laboratory testing.

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PRODUCTION SYSTEM:

Procedures designed to prevent microbiological contamination of drug products

purporting to be sterile are not established and written.

RAW MATERIALS SYSTEM:

Each lot of a component liable to objectionable microbiological contamination is

deficiently subjected to microbiological tests before use.

US FDA issues Form 483 to Hovione API facility in Portugal

The US FDA’s pre-approval inspection at Hovione’s API plant in Loures, Portugal,

covering two NDA filings, resulted in a Form 483 with three inspectional observations.

The five day inspection carried out by investigators Ramon Hernandez and Jose Lopez Rubet

still confirmed the site to be compliant with the principles and guidelines of Good Manufacturing

Practices (GMP), but the company did not disclose what the inspectional observations were.

"Addressing these observations is the top priority of the site management and the points raised

will be replied to within 15 working days from the receipt of the Form 483,‖ Luisa Paulo,

Hovione's Compliance Director, said. ―We are taking this result to improve our quality system

both here and at our other sites. The investigators spoke positively of many of our initiatives.‖

Back in 2009, the same site was approved by the FDA without any deviations or Form 483s.

Earlier this year, Guy Villax, CEO of Hovione, also questioned the quality of products coming

out of China and India , noting that audit reports need to be shared more widely.

―We have a culture of quality that puts patient safety first. This shapes our behaviors and

motivates us to improve. This is a team effort, and I am very encouraged to see everyone so

committed,‖ said Villax.

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Impax Hit With Another FDA 483

Impax Laboratories was hit with its second FDA 483 recently on its plant in Hayward CA. This

follows an inspection and 483 for its plant in Taiwan earlier this year.

This latest 483 came just a few months after Impax stated that it was confident that its

manufacturing processes were good enough to resubmit an NDA for a drug for Parkinson‘s

disease. The approval for that drug had been delayed due to concerns from FDA about the

firm‘s cGMP controls.

In the most recent 483, two of the observations were repeats from the first inspection, which is

something FDA particularly frowns upon.

In 2013, the company had to let go over 100 employees at the plant in CA because GMP

problems there led GSK to abandon a $180 million partnership with Impax.

The Hayward CA 483 stated that the firm had many pyridostigmine tablets that were not in

spec. After they ruled out lab errors, the plant failed to determine if there was a problem in the

manufacturing of the pills, and released the product.

Also criticized in the FDA report was plant maintenance, which noted that ceiling tiles were

sagging, there was a rusty drain and several problems with a walk in chamber that is used for

stability studies and storing product.

Repeat 483 violations concerned not having sufficient protections in place to be sure analysts

cannot rewrite and/or delete data during an analysis.

This plant in Hayward has been a major problem for Impax in the last few years. cGMP

violations led to a warning letter being issued in 2011.

At the Taiwan plant, observations included validation related problems and also problems with

testing during the production of Rytary.

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FDA Warning letters

Novacyl Wuxi Pharmaceutical Co., Ltd. 12/19/14 (WL: 320-15-04):

API: CGMP DEVIATION

1. Failure to manage laboratory systems with sufficient controls to ensure

conformance to established specifications and prevent omission of data.

Serious deficiencies related to your documentation practices, including missing raw data.

the analyst discarded the chromatogram because it was present in the blank

injection. However, the analyst was unable to retrieve the blank chromatogram from the system

because it was overwritten by a subsequent injection.

changes to integration parameters for the impurities test without appropriate documentation or

justification.

Your firm relied upon hand written notes on a chromatogram discovered in a drawer at the

laboratory as the documentation for this change. Furthermore, your firm implemented this

change without an audit trail that would have captured the date of the change and who made

the change.

Other significant deficiencies noted in your laboratory system include:

a) Failure to have a written procedure for manual integration despite its prevalence.

b) Failure to use separate passwords for each analyst‘s access to the laboratory systems.

c) Use of uncontrolled worksheets for raw analytical data in your laboratory.

d) Presence of many uncontrolled chromatograms, spreadsheets and notes of unknown origin found in a drawer.

FINISHED PRODUCT: CGMP VIOLATIONS

2. Your firm did not properly document or investigate out-of-specifications (OOS) and

other discrepancies(21 CFR 211.192).

For example, the inspection documented that OOS Investigation #1203, related to the presence

of metal particles in (b)(4), failed to determine the root cause of the contamination or explain

why the (b)(4) step was unable to prevent the contamination.

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3. Your firm failed to establish laboratory controls that include scientifically sound and

appropriate specifications, standards, sampling plans, and test procedures designed to

assure that components, drug product containers, closures, in-process materials,

labeling, and drug products conform to appropriate standards of identity, strength,

quality, and purity (21 CFR 211.160(b)); and,

4. Your firm did not record all CGMP activities at the time these were performed. The

lack of contemporaneous documentation of CGMP activities increases the likelihood of

recording erroneous data(21 CFR 211.188). your firm failed to ensure testing documentation was complete and accurate.

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AUDIT FINDINGS - EMA Non Compliance Reports Non Compliance Report: Medreich Limited – Unit V:

Site address : Plot n°45 A & B, Anrich Industriel Estate, Bollaram, Medak District, Andra Pradesh, 502325, India From the knowledge gained during inspection of this manufacturer, the latest of which was conducted on 2014-05-16 , it is considered that it does not comply with the Good Manufacturing Practice requirements referred to in "The principles and guidelines of Good Manufacturing Practice laid down in Directive 2003/94/EC". Nature of non-compliance : 58 deficiencies have been raised during the inspection which was a follow-up of the inspection conducted from 28 January 2013 to 1 February 2013 (see NCR/HPF/FR/1/2013). 1 deficiency related to data falsification has been classified as "critical" . 29 deficiencies have been classified as "major". Among them, - 5 were related to poor level of quality management (inadequate deviations management system with no exhaustive record, no classification and no thorough investigation), - 3 were related to personnel (no formal policy on temporary workers specially for quality critical activities such as visual inspection), - 5 were related to the maintenance of equipment (depyrogenisation tunnel and RABS used for the filling operation, LAF used for the sampling of sterile starting materials ...), - 4 were related to documentation (documentation management and data integrity with difficulty to demonstrate that the actions recorded were genuine), - 9 were related to production (sterile and non-sterile products) including risk of cross contamination, poor visual inspection process handling, poor in-process control handling (weight of vials, weight of tablets and hard capsules), poor handling of broken vials issues.

Non-Compliance Report: Sri Krishna Pharmaceuticals Ltd., Hyderabad, India

Nature of non-compliance : During the inspection 10 Major deviations from EU GMP have been found. In particular, main

concerns were:

1. Drug products failing to meet established quality control criteria are not rejected. In particular:

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a) analysts routinely use the PC administrator privileges to set the controlling time and date

settings back to over-write previously collected failing and/or undesirable sample results. This

practice is performed until passing and/or desirable results are achieved;

b) Analysts routinely perform ―trial‖ injections of sample aliquots prior to performing the

official/reported analysis. There are no documented sample preparation details for these trial

analyses. The results of these trial injections are not reported, and were found to differ

significantly from the subsequent reported results;

c) Analysts routinely perform ―trial‖ injections of sample aliquots prior to performing the

official/reported analysis. The resulting raw data chromatogram files were often found to have

been deleted and unavailable for review;

d) Analysts delete undesirable and/or failing results (entire sample sequences) and retest

samples until desirable results are achieved.

2. Established laboratory control mechanisms are not followed. Electronic records are used, but

they do not meet systems validation requirements to ensure that they are trustworthy, reliable

and generally equivalent to paper records;

3. Missing or poor quality agreement;

4. Written production and process control procedures are not documented at the time of

performance. Specifically, Too Numerous to Count (TNTC) torn and discarded controlled

manufacturing batch records for a variety of different products issued by the Quality Unit were

found during a walk-through inspection of the facility. Five batch records were compared with

the archived manufacturing one and it was ascertained that no records had been made for

duplicate issuance of these five batches chosen for review, as required per SOP

QA/SOP/DOC/001. Notably, after subsequent investigation it was found that the Master Batch

Record (version 0) had been back-dated by the most responsible persons within your firm‘s

Quality and Manufacturing departments, which was confirmed by these persons during our

inspection.

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Check your area for ….

Are all protocols, methods, reports, etc. are

written, reviewed approved and filed where they are secure, but easily retrieved?

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Regulations of the Month

Subpart J--Records and Reports

§ 211.188 Batch production and control records.

Batch production and control records shall be prepared for each batch of drug product

produced and shall include complete information relating to the production and control of

each batch. These records shall include:

(b) Documentation that each significant step in the manufacture, processing, packing, or

holding of the batch was accomplished, including:

(4) Weights and measures of components used in the course of processing;

(5) In-process and laboratory control results;

(6) Inspection of the packaging and labeling area before and after use.

(7) A statement of the actual yield and a statement of the percentage of

theoretical yield at appropriate phases of processing.

(8) Complete labeling control records, including specimens or copies of all

labeling used.

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